Simple tools for characterizing functional vulnerability after cholecystectomy are lacking, particularly among patients referred for outpatient rehabilitation. We examined whether a cumulative count of routine nutritional, inflammatory, and redox-related biomarker abnormalities at the first physical medicine and rehabilitation (PM&R) visit was associated with 12-week physical performance. This single-center retrospective cohort included 184 adults assessed 14–180 days after cholecystectomy. The exposure counted abnormalities in zinc, 25-hydroxyvitamin D, homocysteine, albumin, and neutrophil-to-lymphocyte ratio. The primary outcome was the 12-week Short Physical Performance Battery (SPPB) total score. After multivariable adjustment, each additional abnormality was associated with a 0.49-point lower 12-week SPPB score (β = −0.49, 95% confidence interval = −0.80 to −0.18; p = 0.002). Supportive analyses showed higher odds of low physical performance, lower odds of substantial SPPB improvement, lower grip strength, and a shorter 6-min walk distance. The additional explanatory value was modest (incremental R2 = 0.03). A higher routine biomarker abnormality burden may characterize postoperative vulnerability relevant to rehabilitation assessment, but the count is not a validated prediction or treatment selection tool and requires prospective validation.
Osteoclasts are the primary bone-resorbing cells responsible for maintaining skeletal homeostasis through balanced bone remodeling. Accumulating evidence suggests that oxidative stress is an emerging regulator of osteoclast differentiation, metabolic reprogramming, and bone resorption, arising from excessive reactive oxygen species (ROS) and insufficient antioxidant defenses. Dysregulated redox signaling contributes to osteoporosis, rheumatoid arthritis, periodontitis, periapical lesions, and other osteolytic disorders. This review summarizes recent advances in the molecular mechanisms linking oxidative stress to osteoclast metabolism, focusing on ROS sources, mitochondrial dysfunction, redox-sensitive signaling pathways, endogenous antioxidant systems, and emerging antioxidant-based therapies. Oxidative stress regulates osteoclastogenesis through interconnected signaling networks, including NF-κB, MAPKs, PI3K/Akt, AMPK, mTOR, NFATc1, and Keap1/Nrf2. Under both physiological and pathological conditions, osteoclast function is regulated by mitochondrial dynamics, mitophagy, and epigenetic mechanisms. Although both synthetic and natural antioxidants have been shown to reduce pathological osteoclast activity in preclinical studies, limitations in bioavailability, target specificity, and long-term efficacy hinder clinical translation. Advances in multi-omics technologies, single-cell analyses, biomarker discovery, precision medicine, and targeted antioxidant delivery may facilitate the development of effective therapies for oxidative stress-related bone disorders.
Periodontitis is a prevalent chronic inflammatory disease characterized by gingival inflammation and progressive alveolar bone loss. The NLRP3 inflammasome functions as a molecular mediator that drives its pathogenesis. Bergapten (BeG), a natural furanocoumarin, exhibits anti-inflammatory properties and bone-protective effects. This study demonstrates that BeG alleviates experimental periodontitis in mice by inhibiting the NLRP3 inflammasome. Mechanistically, BeG does not affect NLRP3 priming, dispersed trans-Golgi network (dTGN) localization, or oligomerization; instead, it induces mitophagy by inhibiting the AKT–mTOR axis and consequently suppresses the mtROS-dependent NEK7–NLRP3 interaction. Notably, BeG also suppressed cytosolic release of oxidized mitochondrial DNA (ox-mtDNA), a known endogenous ligand for NLRP3. This effect was attributed to BeG-mediated inhibition of NLRP3 activation, likely via blockade of GSDMD-NT mitochondrial localization. These findings deepen our understanding of the anti-inflammatory mechanisms of BeG and position it as a promising candidate for periodontitis treatment.
Although ferroptosis is a programmed iron-dependent cell death, many lipophilic iron complexes fail to induce ferroptosis through iron overload. The underlying mechanisms remain unclear. Here we found that a typical lipophilic iron complex 8-hydroxyquinoline (8HQ)-Fe(III) (1: 1, 10 μM), can efficiently induce cellular iron overload, lipid peroxidation, and finally cytotoxicity. However, the resulting cell death mode was not typical ferroptosis: it was not inhibited by the classic ferroptosis inhibitors and exhibited mitochondrial swelling rather than shrinkage. Mechanistic studies revealed that 8HQ-Fe(III) triggered both endoplasmic reticulum (ER) peroxidation and mitochondrial damage. The ER-targeted antioxidant (stobadine) inhibited lipid peroxidation but did not suppress cell death. In contrast, mitochondrial protectants effectively blocked 8HQ-Fe-induced cell death by mitigating mitochondrial damage. This indicates that mitochondrial damage plays an overwhelmingly dominant role in driving cell death. Strikingly, pre-incubation with docosahexaenoic acid (DHA) can strongly enrich the ER membrane and increase its peroxidation. As expected, both stobadine and the well-known ferroptosis inhibitor (Fer-1) suppressed 8HQ-Fe(III)-induced cell death via inhibition of ER peroxidation, while mitochondrial protectants failed to prevent cell death. Mitochondrial shrinkage was also observed. Thus, making ER peroxidation the dominant driver of cell death by DHA pretreatment will switch the cell death modality from non-ferroptosis to classical ferroptosis. This study revealed that the balance between ER peroxidation and mitochondrial damage dictated the type of iron-dependent cell death, and established DHA-primed 8HQ-Fe(III) as a novel, tunable strategy for efficiently inducing ferroptosis by deliberately shifting subcellular peroxidation dominance.
Oxidative stress-induced impairment of chondrocyte differentiation and bone homeostasis is pivotal in tibial dyschondroplasia (TD). Sodium butyrate has been shown to modulate gut microbiota, improve redox homeostasis, and support skeletal metabolism; however, whether it exerts protection against TD specifically through oxidative stress modulation remains unclear. A total of 210 one-day-old male Arbor Acres broilers were randomly allocated to three treatment groups, with seven replicate pens per group and 10 birds per pen. The birds were housed in a windowless, climate-controlled indoor poultry house with floor pens and rice-husk bedding. In a thiram-induced broiler TD model, dietary sodium butyrate (500 mg/kg) reshaped the gut microbiota by increasing beneficial genera (Ligilactobacillus, Lactobacillus, Blautia, and Mediterraneibacter), decreasing Escherichia-Shigella abundance, and elevating ileal butyrate concentration. These shifts co-occurred with mitigated oxidative damage, including reduced ROS and MDA in both serum and ileal mucosa, partial elevations in SOD and GSH-Px activities, upregulated Nrf2 and HO-1 expression in both the ileal mucosa and tibial growth plate, and improved mitochondrial function in the ileal mucosa, as indicated by restored mitochondrial membrane potential, reduced superoxide anion levels, and increased respiratory chain complex I activity. Concomitantly, sodium butyrate improved growth performance and skeletal phenotypes, attenuating growth plate lesions and restoring tibial morphology and mineralization. It also favorably modulated bone metabolism by elevating the OPG/RANKL ratio and upregulating COL2A1 expression. Correlation analyses linked microbial alterations to antioxidant status and skeletal parameters. Collectively, these findings suggest that sodium butyrate alleviates thiram-induced TD in association with gut microbiota remodeling, which is correlated with enhanced redox homeostasis and bone metabolism, supporting a potential gut–bone axis mechanism.
